The Discovery of GSK2251052: A First-in-Class Boron ... - Anacor

The Discovery of GSK2251052: A First-in-Class
Boron-Containing Antibacterial Agent Targeting
Leucyl tRNA Synthetase
Vincent Hernandez
Director, Medicinal Chemistry
Anacor Pharmaceuticals, Inc. Palo Alto, CA
vhernandez@anacor.com

2
Talk Summary
GSK2251052
Drug resistant bacteria are a global threat to health care
– Resistance is a natural response to the selective pressure caused by antibiotic use
– New drugs, and particularly new drug classes, are desperately needed to combat
existing clinical resistance
Target-based HTS was not successfully applied to antibacterial research
– Most antibiotics are based on natural products
– Antibacterial ‘drug space’ is different from other therapeutic areas
– New approaches (or chemistries) are needed
Boron is underexploited in medicinal chemistry and has tremendous potential in
drug discovery
GSK2251052 inhibits bacterial Leucyl tRNA synthetase and represents a new
class of Gram-negative antibacterial agents
This novel mechanism of action means GSK2251052 is not affected by existing
modes of target-specific clinical resistance
GSK2251052 is the first novel mechanism of action agent to reach Phase II
clinical development for the treatment of Gram-negative bacterial infections in
30 years

Bacterial Infections in Pre-antibiotic Times
3

4
Antibiotic Resistance is a Global Threat to
Healthcare Today

5
Antibiotic Resistance is Increasing But New
Drug Approvals are Continuing to Decline
BIG PHARMA
BIG PHARMA
Modified from Cooper and Shlaes Nature 2011, 472, 32
We desperately need novel MOA drugs to combat bacterial resistance
Much of Big Pharma has left antibacterial drug discovery to pursue
more lucrative indications

Lack of Novel Antibiotics that Target New
Mechanisms in Gram-negative Bacteria
1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Penicillin
(β-Lactams)
PBP
Protosil
(Sulfonamides)
DHPS
Streptomycin
(Aminoglycosices)
30S Ribosome
Chloramphenicol
50S Ribosome PTC
Fosfomycin
MurA
Trimethoprim
DHPS
Nalidixic acid
(Quinolones)
Topoisomerase
Mupirocin
IleRS
Lincomycin
(Lincosamides)
50S Ribosome PTC
Daptomycin
Cell Membrane
Linezolid
(Oxazolidinones)
50S Ribosome PTC
Polymixin B
LPS
Chlortetracycline
(Tetracyclines)
30S Ribosome
Pleuromutilin
50S Ribosome PTC
Novobiocin
Gyrase
Erythromycin
(Macrolides)
50S Ribosome PTC
Vancomycin
D-Ala-D-Ala
!
Modified from Lynn Silver (2011) Clinical Microbiology Reviews 24: 71–109
6

Genomic Revolution did not Improve Antibacterial Lead
Identification: Results of GSK’s Target-based HTS
70 HTS were conducted on the most
promising essential gene targets
GSK library contained ~500K
compounds
Only 16 HTS campaigns yielded any hits
Only 5 leads were developed
– Peptide deformylase (PDF)
– Enoyl-acyl carrier protein reductase (FabI)
– 3-ketoacyl-acyl carrier protein III (FabH)
– Methionyl tRNA synthetase (MetRS)
– Phenylalanyl tRNA synthetase (PheRS)
Better leads already existed for PDF
FabI and MetRS were not broad
spectrum and subsequently partnered
with biotech
FabH did not advance beyond lead
Only PheRS was pursued
7
Nat Rev Drug Discov. 2007;6,29-40

Antibacterials Occupy a Different ‘Drug
Space’
•CNS drugs closely follow Lipinski’s rules
•Antibacterials are on average more hydrophilic and larger
8
Nat Rev Drug Discov. 2007;6,29-40

Boron Chemistry: A New Approach to Drug Discovery

10
Boron is Commonly Found in Our
Environment
In nature, boron is present as boric acid
Boric acid is the main ingredient of Goop
–Children’s brightly colored toy, that they
squeeze through their fingers
Boric acid is used as a preservative in eye
wash and vaginal creams
Boric acid has an LD 50 similar to regular
table salt (~3000 mg/kg)
Boron is an essential plant nutrient
We consume up to 4 mg of boron a day,
primarily from fruits, vegetables and nuts
At Anacor, we found background levels of
200 ng/mL of boron in mouse plasma

11
General Facts on Boron
Boron is commonly found as boric acid in our living environment
Boron is similar to carbon in that it can form stable covalent bonds,
including carbon-boron bonds
Boron has a unique geometry and reactivity with an empty P-orbital

12
Boron has a Unique Bonding Orbital
Configuration: An Empty P-Orbital
Trigonal Planar
Tetrahedral
Boron has an empty p-orbital & can form a dative bond
under specific conditions
The dative bond forms a tetrahedral structure
Exploitation of p-orbital expands drug design possibilities

History and Overview of Boronic Acid Drug
Discovery Efforts
Design of boronic acid enzyme inhibitors initiated in 1980s
Multiple disease targets have been pursued
H 2 N
NH
N
H
O
OH
B
OH
NH
O
N
Thrombin
Dup 714
NHAc
β-Lactamase Inhibitor
Arginase Inhibitor
HCV Pr Inhibitor
DPP4 Inhibitor – PHX-1149
Only Velcade has reached FDA approval
Velcade
Baker et al. (2009) Future Medicinal Chemistry, 1(7), 1275-1288
13

14
Classical Boronic Acids Have Significant
Limitations
O
H
N
OH
B OH
Most boronic acid enzyme
inhibitors contain an aliphatic
carbon-boron bond
Consequences of an aliphatic carbon-boron bond
–Chemical reactivity is moderate and can lead to over reactivity
with non-target proteins – poor selectivity & specificity
–Stability problems often arise via oxidation or proto-deborination
–Oxidative metabolism can lead to elimination of boron and loss
of biological activity
–pKa range of 8-9 favors trigonal form in aqueous environment
–Can pose synthetic challenges

15
Anacor’s Approach to Drug-like Chemical Matter
Create new organo-boron compounds that retain
the P-orbital reactivity but with greatly enhanced
chemical and metabolic stability

16
Benzoxaboroles Show Better Drug-like
Properties Compared to Boronic Acids
pK a range of 9-10, indicating
weaker Lewis acid and poorer
water solubility
Freely rotated C-B bond is easily
accessible to nucleophiles, prone
to non-specific binding or selfaggregation
Aliphatic boron activity (potency,
selectivity) can be difficult to
modulate
Stability & metabolism issues
Well known in the literature
pK a range of 7-8, indicating
stronger Lewis acid and better
water solubility
Constrained C-B bond in a fused
ring is more specific & reactive to
targeted nucleophiles, and less
prone to non-specific binding
Potency/selectivity can be easily
fine-tuned by electronic and
steric effects of substitutents
Chemically & metabolically stable
Underexploited in MedChem

17
Re-discovery of the Benzoxaboroles
Early chemical exploration at Anacor of a series of borinic
esters led to the isolation of a cyclic boronic ester
R
Br
O
O
O B O
nBuLi
R
B
OH
O
O
R 2
R 2 R2
HCl
MeOH
R
B
O
O
B
O
O
O
O
nBuLi
O
O
B
OH
O
O
O
HCl
MeOH
O
B
O
OH
B
O
O
Desired Compound
Isolated Compound

AN2690 (Tavaborole) has Broad-spectrum
Antifungal Activity
Yeast MIC
AN2690
(µg/mL)
S. cerevisiae ATCC 201388 0.12
C. albicans ATCC 90028 0.5
C. albicans (fluconazole resistant) 0.5
C. glabrata ATCC 90030 0.12
C. krusei ATCC 44507 1
C. parapsilosis ATCC 22019 ≤ 0.5
C. tropicalis ATCC 13803 ≤ 0.5
C. neoformans F285 0.25
M. fufur ATCC 44344 1
M. pachydermatis ATCC 96746 1
M. sympodialis ATCC 44031 1
Mold MIC
AN2690
(µg/mL)
A. fumigatus ATCC 13073 0.25
R. microsporus ATCC 66276 2
A. alternata ATCC 6663 0.5
P. chrysogenum ATCC 10108 2
C. cladosporioides ATCC 16022 0.5
Fusarium solani ATCC 36031 2
Dermatophyte MIC
AN2690
(µg/mL)
T. rubrum (MIC 90 ) 8
T. mentagrophytes (MIC 90 ) 8
T. tonsurans ATCC 28942 2
E. floccosum ATCC 52066 ≤ 0.5
M. audouinii ATCC 42558 2
M. canis ATCC 10214 2
M. gypseum ATCC 24103 2
Currently in phase III trials for the topical treatment of onychomycosis
Baker et al.(2006) J. Med. Chem. 49: 4447-4450
18
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19
AN2690 (Tavaborole) was Shown to be Efficacious
and Well Tolerated in Phase 2 Clinical Trials
Efficacy
Boron-based compound
– Targets LeuRS to kill fungus
– Physical properties of
molecule enables nail
penetration
Baseline
Demonstrated efficacy in three
Phase 2 trials
Safety
Day 180
Topical drug
Little or no detectable systemic
exposure
All preclinical toxicology
completed

20
Antifungal Tavaborole Validated Leucyl tRNA
Synthetase as a Novel Drug Target
F
OH
B
O
AN2690
Tavaborole
Genetic study in
Saccharomyces cerevisiae
identified the cytoplasmic
LeuRS gene (CDC60)
LeuRS has two active sites
• Editing site
• Synthetic site
All mutations mapped to
the editing domain
Rock et al. Science 2007, 316, 1759-1761

21
Leucyl-tRNA synthetase (LeuRS)
Editing
domain
tRNA Leu
C-terminal
domain
Anticodonbinding
domain
LeuRS-tRNA Leu crystal
structure at 2.3 Å
Catalytic
domain
Leucylspecific
domain
The aminoacyl-tRNA synthetase LeuRS is
essential for protein synthesis
- Attaches leucine to the 3’ terminal nucleotide
of tRNA Leu (A76)
Two active sites separated by 38 Å
- Synthetic active site synthesizes
aminoacylated tRNA Leu
- Editing (proof-reading) active site
- A76 moves between the two active sites
Editing site ensures fidelity of protein
synthesis
- Synthetic site can attach isoleucine, valine,
methionine, norvaline and other amino acids
to tRNA Leu
- Editing site hydrolyzes all aminoacyl-tRNA Leu
other than leucine
- Mischarged tRNA Leu are extremely deleterious
to the cell

22
Bacterial and Eukaryotic LeuRS are Different
Archeal/
Eukaryotic
editing
catalytic
HIGH
15 % id.
KMSKS
ABD
C-ter1
A
C
C
A
editing
LS
A
C
C
A
Bacterial
HIGH
catalytic
KMSKS
ABD
C-ter2
28 % identity
Mitochondrial LeuRS is editing defective
- (Lue & Kelly Biochem (2005) 44: 3010)

X-ray Structure Revealed A tRNA Leu Adduct in
the Editing Site of Leucyl tRNA Synthetase
AN2690-A76 Adduct
In Editing Site
Leucine
in
Synthesis Site
tRNA
O
O
P
O -
O
O
N
N
NH 2
N
N
O
O
B
O
F
LeuRS
Rock et al. (2007) Science 316:1759-1761
23
tRNA Leu

24
AN2690 Forms a Bi-dentate Adduct to the
Terminal Ribose of tRNA leu
Rock et al. Science 2007, 316, 1759-1761

AN2690 Traps tRNA Leu in Editing Site and
Inhibits Aminoacylation
Prevents aminoacylation of
tRNA Leu , which ultimately leads
to a block in protein synthesis
Boron is absolutely essential
Carbon and other analogues
are inactive
AN2690-tRNA Leu
Rock et al. Science 2007, 316, 1759-1761.
25 25

Benzoxaborole Ring is Essential for
Inhibition of Fungal LeuRS
Structure IC50 (μM) Structure IC50 (μM)
2.1 >100
96 >100
>100 >100
>100
Boron and the oxaborole ring
are required for inhibition of
aminoacylation.
Rock et al. Science 2007, 316, 1759-1761.
26

27
AN2690 had Poor In vitro Activity Against
Gram-negative Bacteria
IC 50
*(µM)
MIC (µg/mL)
Compound
E. coli
P. aeruginosa
S. cerevisiae
Acinetobacter
sp. ATCC15473
E. coli K12
K. pneumoniae
ATCC 700603
P. aeruginosa
ATCC 27853
AN2690
F
OH
B
O
9.9 7.9 0.06 32 8 32 >64
AN2690 showed poor biochemical potency and weak bacterial MIC
profiles
- E. coli LeuRS off-rate was very fast
X-ray structure of AN2690/LeuRS suggests that more interactions
could be obtained by incorporating appropriate substituents
* IC 50 determined after 20 minutes pre-incubation with enzyme and tRNA

X-ray Structure of AN2690 in Bacterial LeuRS
Revealed a Key Binding Site was not Utilized
Tyr-327
Leu-329
Tyr-327
Leu-329
Asp-347
Ile-337
Asp-347
Ile-337
Val-340
Thr-252
Met-338
Tyr-332
Thr-248
Val-340
Thr-252
Met-338
Thr-248
Norvaline post-transfer substrate analogue
AN2690-AMP
Lincecum et al. Molecular Cell 2003, 11, 951-963 Rock et al. Science 2007, 316, 1759-1761
28

29
3-Aminomethyl Substitution was Added
to Gain These Key H-bonds
Nva2aa
AN2690
Nva2aa
AN3334

Addition of 3-Aminomethyl to Benzoxaborole
Made Three Hydrogen Bonds with LeuRS
Leu-327
Asp-345
Asp-342
Glu-329
Val-338
Tyr-330
E. coli LeuRS IC 50
Thr-252
Met-336
Thr-248
27.5 μM
Thr-247
Ser-227
1.0 μM(AN3334)
Alley et al. ICAAC 2009 F1-1223a
30

31
Improving Spectrum of Activity for AN3334
Was Focus of Lead Optimization
Strain
No. of
strains
AN3334
Tigeccyline
Imipenem
P. aeruginosa (WT) 50 1 16 1 8 2 4 16 32 >64 >64
P. aeruginosa (MbL-) 25 1 >16 32 >32 >16 >16 >32 >128 >64 >64
P. aeruginosa (MbL+) 26 1 >16 >64 >32 >16 >16 >32 >128 >64 >64
A. baumannii (WT) 25 >128 1 0.25 8 4 2 16 8 32 32
Acinetobacter spp. (MDR) 26 >128 8 64 >32 >16 >16 >32 >128 >64 >64
S. maltophilia (WT) 50 1 1 >64 >32 4 >16 >32 >128 >64 >64
B. cepacia 50 4 4 16 32 8 >16 16 32 >64 >64
E. coli (WT) 27 1 0.25 0.12 ≤1 >16 2 ≤1 8 32 >64
E. coli (ESBL) 25 2 0.25 0.25 >32 >16 >16 >32 128 64 >64
Klebsiella spp. (WT) 25 1 0.5 0.25 ≤1 ≤0.5 1 ≤1 16 8 >64
Klebsiella spp. (ESBL) 15 1 2 1 >32 16 >16 >32 >128 64 >64
Klebsiella spp. (KPC) 10 2 1 >64 >32 >16 16 >32 >128 >64 >64
Enterobacter spp. (WT) 25 1 0.5 1 ≤1 ≤0.5 ≤0.5 2 8 >64 >64
Enterobacter spp. (AmpC) 26 1 4 0.5 8 >16 >16 >32 >128 >64 >64
Citrobacter spp. (WT) 36 1 0.5 1 ≤1 1 >16 2 16 >64 >64
Citrobacter spp. (AmpC) 16 0.5 0.5 1 2 16 2 >32 128 >64 >64
P. mirabilis (WT) 42 128 4 2 ≤1 2 2 ≤1 0.5 8 >64
P. mirabilis (ESBL) 11 >128 4 2 >32 >16 >16 >32 4 64 >64
P. vulgaris (WT) 20 >128 2 2 ≤1 ≤0.5 1 ≤1 0.5 16 >64
M. morganii (WT) 17 2 2 4 ≤1 4 2 4 2 >64 >64
Indole positive Proteae 14 16 2 2 ≤1 16 4 ≤1 4 >64 >64
S. marcenscens (WT) 38 0.5 1 1 ≤1 1 1 2 32 >64 >64
S. marcenscens (AmpC) 16 0.5 2 1 4 4 >16 >32 64 >64 >64
Key: Red = resistant, Yellow = intermediate and Green = susceptible based on CLSI interpretive criteria (M100‐S21, 2011), except for
AN3334 (susceptible defined as MICs ≤4 mcg/mL), tigecycline (FDA interpretive criteria used to define susceptibility) and polymixinB
(susceptible ≤ 2mcg/mL , intermediate 4 mcg/mL, resistant ≥8 mcg/mL)
Cefepime
Levofloxacin
Gentamicin
Ceftazidime
Piperacillin/
tazobactam
Amoxycillin/
clavulanate
Ampicillin

32
7-Hydroxyl Substitution Identified Another
Interaction with Phosphate of tRNA
Asp-342
Asp-342
P75
Leu-327
Glu-329
E. coli LeuRS IC 50
Thr-252
Met-336
Thr-248
Tyr-330
Ser-227
27.5 μM
Thr-247
1.4 μM (AN3016)

33
Key Interactions Identified in X-ray Structures
were Combined in AN3365/GSK2251052
OH
OH
OH
B
O
AN3334
NH 2
+
O
AN3016
OH
B
O
O
OH
B
O
NH 2
GSK2251052
A 76
Arg 344
A 76
A 76
Thr 248
Asp 342
Thr 248
Arg 344
Thr 248
Asp 342
Asp 345
Thr 247
AN3334
Asp 345
Thr 247
AN3016
Asp 345
Asp 342
Thr 247
GSK2251052
Hernandez et al. ICAAC 2010 F1-1637

34
GSK2251052 has Broader Spectrum than AN3334 with
Activity Against Proteae and Acinetobacter in Primary Panel
E.coli
K.pneumoniae
Compound LeuRS IC50 ATCC29522 CTM-2,OXA-2 K12 WT K12 tolC ATCC42816 KPC2 ATCC27853 PA01 WT PA01 pumpless ATCC15473 BAA1710 IMP BAA-663
Ciprofloxacin N/A 6.4
Meropenem N/A 64
Tigecycline N/A 64 0.5 0.5 0.25 1 >64 8 >64
AN3334 1.0 uM 1 1 2 2 1 0.5 2 2 1 >64 >64 2 >64
AN3016 1.36 uM 4 16 8 2 16 16 >64 >64 8 4 8 NT 32
GSK'052 0.31 uM 1 1 2 2 1 1 2 1 0.5 1 2 1 1
4 >100 uM 64 >64 >64 >64 64 64 >64 >64 64 >64 >64 NT >64
P.aeruginosa
A.baumannii
E.cloacae
P.mirabilis
FDA approved breakpoints for tigecycline and CLSI susceptibility criteria were used (green=S, yellow=I,
red=R). Polymyxin B breakpoints for P. aeruginosa were used for Enterobacteriaceae. For the Anacor
compounds they were color coded as green ≤ 4 ug/mL, yellow = 8-16 µg/mL, Red ≥32 µg/mL.

35
GSK2251052 In Vitro Activity: Enterobacteriaceae,
Including Multidrug-Resistant Strains
Key: Red = resistant, Yellow = intermediate and Green = susceptible based on CLSI interpretive criteria (M100‐S21,
2011), except for GSK2251052 (susceptible defined as MICs ≤4 mcg/mL), tigecycline (FDA interpretive criteria used
to define susceptibility) and polymixinB (susceptible ≤ 2mcg/mL , intermediate 4 mcg/mL, resistant ≥8 mcg/mL)

36
GSK2251052: Pre-Clinical In vitro
Frequency of Resistance
Compound
Frequency of Resistance
E. coli K. pneumoniae P. aeruginosa
4xMIC 10xMIC 4xMIC 10xMIC 4xMIC 10xMIC
GSK2251052 8x10 ‐8 6x10 ‐8 5x10 ‐8 4x10 ‐8 1x10 ‐7 5x10 ‐8
2x10 ‐7 7x10 ‐8 8x10 ‐7 6x10 ‐8 2x10 ‐7 9.6x10 ‐8
1x10 ‐7 8x10 ‐8 4x10 ‐8 2x10 ‐8
Ceftazidime

37
GSK2251052: Pre-Clinical Mechanism
of Resistance
Laboratory generated mutants resistant to GSK2251052 contain mutations
in the LeuRS editing domain
– Single-step mutations in leuS
GSK2251052 MICs of resistant mutants range from 32->256 mcg/mL
Organism
GSK2251052 MIC (mcg/ml)
WT
Mutants
E. coli 1 64‐>256
K. pneumoniae 1 256‐>256
P. aeruginosa 4 32‐>256
– GSK2251052 resistant mutants do not confer cross-resistance to other
antibiotics and appear to be editing deficient

Synthesis of GSK2251052

39
Initial Medchem Synthesis Relied on Chiral
Prep-HPLC Separation of Enantiomers

40
Improved Medchem Process was used to
Produce Phase I Clinical Trial Material
OH
OH
BnO
Br
O
OH
OBn
Tf 2 O, Pyridine
O
OTf
OBn
CHO
t-BuONa, DMSO
rt, O/N
quantitative
CHO
DCM, rt, 3 h
64-88%
CHO
O O
BB
O O
PdCl 2 (dppf), KOAc
THF or dioxane
50-75%
BnO
O
OH
B
O
NaOH(aq.), CH 3 NO 2
THF, 0 o Ctort,O/N
55-60%
BnO
O
O
B O
CHO
NO 2
50% yield
1)Pd(OH) 2 ,NH 3 in MeOH
2) HCl in MeOH
HO
O
AN3213
(racemic)
OH
B
O
NH 2 .HCl
HO
1) NH 3 in MeOH
2) R-(-)-mandelic acid
3) aq. HCl
47% yield
O
GSK2251052
OH
B
O
NH 2 .HCl

41
Process Research at GSK Identified a
Stereospecific Route to GSK2251052
Conde, JJ. WO 2011127143

Systemic Treatment with GSK2251052 Shows Good
Distribution with no Accumulation in Tissues
Figure 1. Whole-body autoradiograph for male Long Evans Rat at 1, and 72 h after a
single intravenous administration of 14C-GSK2251052 (Group 5, 50 mg/kg)
Liu et al. N. American Regional ISSX 2011 P-84
42

43
GSK2251052 Phase 1 Results Showed Linear PK
with Blood Levels Reaching in Excess of MIC90 Levels
IV Dose
Mean AUC*
(h.µg/ml)
Mean Cmax*
(µg/ml)
MAD 1 500 mg BID x 8 days 56 9.4
MAD 2 750 mg BID x 14 days 76 11.5
MAD 3 1200 mg BID x 14 days 117 19.1
MAD 4 2000 mg BID x 14 days 193 31
*Mean PK parameter for last day of dosing

Recreating Human PK Profiles in Rat Infection
Models
Rats receive continuous IV infusion via jugular cannula
– Infusion delivered by peristaltic pump
– Flow rates of infusion controlled by computer
– Rates change every 15 minutes to recreate
human concentration profile in rat blood
‘052 tested in lung and thigh infection models
• Blood samples collected to confirm PK profiles
• Animals receive 4 days of therapy
All studies were conducted after review by the Institutional Animal Care and Use Committee at GSK
and in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals
44

45
Efficacy of Recreated Human IV Exposure Profiles
Dosed BID in Rat Lung and Thigh Infection Models
Daily AUC 60 ug.h/ml
Cmax 10 ug/ml
K. pneumoniae ANA588 (lung)
500mg profile for ‘052
Daily AUC 120 ug.h/ml
Cmax 18 ug/ml
MIC=0.5
MIC>64
MIC=0.125
E. coli 343659 (thigh)
500mg profile for ‘052
P. aeruginosa 1483518 (thigh)
1200mg profile for ‘052
MIC>64
MIC>16
MIC>64
MIC=0.5
MIC=0.25
MIC=4

Phase II Clinical Studies
LRS114689: Comparative, dose-ranging study of GSK2251052 vs.
meropenem in in the treatment of complicated intra-abdominal infection
LRS114688: Comparative, dose-ranging study of GSK2251052 vs.
imipenem-cilastatin in complicated lower urinary tract infection and
pyelonephritis
– Both studies are dose ranging , 750mg:1500mg twice a day: Active Comparator
– 210 subjects per study
– Independent Safety Review Committee
– Decide on the most appropriate and safe dose for Phase III
In PH2 cUTI study 4 of 14 patients (20 patients enrolled) saw a rapid
emergence of mutants with high GSK2251052 MIC values
– Mutations were in leuS
In PH2 cIAI study no resistance mutants were discovered in 15 patients
enrolled
Work is ongoing to determine future development options for
GSK2251052
46

47
Talk Summary
Multi-drug resistant bacteria is a global health threat
New approaches are needed to find novel antibacterial agents
Boron is underexploited in medicinal chemistry and has tremendous
potential in drug discovery
AN3365/GSK2251052 inhibits bacterial LeuRS and is the first Gramnegative
antibacterial with a truly novel mechanism of action to reach
phase II trials in over 30 years

Acknowledgements
To Everyone at ANACOR especially
Discovery Biology: M.R.K. Alley, J. Fong,
W. Mao, M. Mohan, M. Meewan, F. Rock,
Pharmacology: P. Torres, H. Sexton,
Y. Freund
Computational Chemistry: Y. Zhou, D.
Sullivan
Medicinal Chemistry: T. Akama, YK
Zhang, Y. Zhang, J. Plattner
PKDM: XQ. Fan, W. Bu, L. Liu
Program Management: S. Lux, S. Baker,
K. Maples
Toxicology: S. Chanda, C. Chen, I. Heyman
Clinical: F. Heerinckx, L. Zane
All studies were conducted after review by the Institutional Animal
Care and Use Committee at GSK and in accordance with the GSK
Policy on the Care, Welfare and Treatment of Laboratory Animals
EMBL: A. Palencia, T. Crepin, S. Cusack
HPA: D. Livermore, M. Warner, S. Mushtaq
NAEJA: J. Nieman, M. Anugula, N. Babu, M. Baek
C. Diaper, C. Ha, M. Kelly, M. Keramane, X. Lu, R.
Mohammad, R. Patnam, K. Savariraj, R. Sharma,
R. Subedi, I. Sidhu, R. Singh
Curragh Chemistries Inc: J. Phillips
Chiral Technologies: L. Cole, E. Esksteen
Chirosolve: N. Vaidya
RICERCA: A. O’Leary
JMI: R. Mendes, D. Biedenbach, H. Sader
R. Jones
IHMA: S. Bouchillon, M. Hackel, D. Hoban
S. Hawser
CMAX/University South Australia:
S. Shakib, R. Milne
Penn State: Steve Benkovic
To Everyone at GSK especially
P. DeMarsh, N. Pearson, E. Dumont, P. Elefante, J. Hoover, C. Jakielaszek, C. Mininger, R. Page, N. Scangarella-
Oman, C. Singley, N. Simon, S. Rittenhouse, J. Tomayko, 48 K. Widdowson, D. Payne, J. Conde, A. Kowalski, M. Zajac 48